Mouth and Genital Ulcers with Inflamed Cartilage Syndrome: Case Report and Review of the Published Work.

Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome are disease that fulfilled criteria for diagnosis of Behcet's disease (BD) and relapsing polychondritis (RP). We report a 22-year-old Japanese woman presented with MAGIC syndrome and we described the clinicopathological characteristics of MAGIC syndrome based on a review of published cases from July 1985 to December 2015. In our case, the patient with oral aphthae, erythema nodosum, acne-like eruptions, uveitis, and polyarthritis fulfilled criteria for diagnosis of incomplete form of BD. The patient with uveitis, polyarthritis, and histological confirmation of chondritis also fulfilled criteria for diagnosis of RP. The patient was successfully treated with oral colchicine followed by prednisolone. The symptoms of MAGIC syndrome gradually disappeared, and the prednisolone dosage was gradually decreased and stopped. She has been in remission without active medication for a further 8 months. In the previous reports, some authors suggested that MAGIC syndrome was not a disease entity and might be RP occurring secondary to BD, another association of an autoimmune disease, or vasculitis with RP. However, the pathogenic association between MAGIC syndrome, BD, and RP is still unclear, and the number of reported cases of MAGIC syndrome is insufficient to establish a clear explanation. Therefore, further accumulation of data and careful observation of the clinical course are required to improve the understanding of MAGIC syndrome.

What was known?

Mouth and genital ulcers with inflamed cartilage syndrome are disease that fulfilled criteria for diagnosis of Behcet's disease and relapsing polychondritis.

Introduction

Behcet's disease (BD)[1] is a multisystemic vasculitis characterized by oral and genital ulcers, aphthous stomatitis, erythema nodosum (EN)-like lesions, papulopustular lesions, uveitis, epididymitis, and neurological symptoms, and involvement of vessels of all sizes, joints, and the gastrointestinal system. Relapsing polychondritis (RP)[1] is an uncommon autoimmune disorder characterized by widespread, destructive, inflammatory lesions of cartilaginous structures, including ear, nose, larynx, trachea, bronchi, peripheral joints, eye, heart, and skin. Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome are disease that fulfilled criteria for diagnosis of BD and RP. It was first proposed by Firestein et al.[1] in 1985. There have been 15 reports of 21 MAGIC syndrome cases in the English-language published work.[123456789101112131415] Herein, we report a case of MAGIC syndrome that was successfully treated with oral colchicine followed by prednisolone and we describe the clinicopathological characteristics of MAGIC syndrome based on a review of published cases from July 1985 to December 2015.

Case Report

A 22-year-old Japanese woman was referred to our department for inpatient hospital care for high fever, oral aphthae, arthralgia in upper and lower extremities, and eruptions on her lower legs that had been present for 3 days. An initial physical examination showed a small painful ulcer in the mouth, multiple painful erythematous, edematous plaques on the anterior aspect of the lower legs, and small erythematous pustular lesions on the back [Figure 1a-c]. She had a body temperature of over 39°C and general malaise. She had no family history including collagen diseases. Laboratory data including complete blood cell count and tests for liver and kidney function were within normal limits. However, the serum levels of C-reactive protein (CRP) (5.6 mg/dL; normal range, 0–0.2 mg/dL) were elevated. The test specific to influenza Types A and B antigens using nasal aspirate samples was negative. The blood and urine cultures were negative. The serum samples were negative for IgM and IgG antibodies against herpes simplex virus. The paired serum samples were negative for IgM and IgG antibodies against coxsackievirus A16. Epstein–Barr virus, rubella virus, and cytomegalovirus showed serological past-infection patterns. The serum antinuclear antibodies and rheumatoid factor were negative, and collagen disease was excluded. A skin biopsy obtained from erythema on the right lower leg showed lobular and septal panniculitis with an inflammatory infiltrate, predominantly composed of lymphocytes, which was consistent with EN [Figure 2a]. EN associated with bacterial infection was suspected. The high fever and eruption tended to improve with intravenous administration of ampicillin hydrate 2 g/day and oral administration of acetaminophen 800 mg/day for 3 days. On day 4, she was discharged from the hospital. However, on day 8, she was hospitalized again because of high fever, general malaise, painful swelling and erythema of the ears [Figure 1d], nose pain, and blurred vision. The blood and urine cultures were negative. Normal results on computed tomography of the head, and normal cerebrospinal fluid values were obtained. Uveitis was diagnosed by an ophthalmologist in our hospital. Human leukocyte antigen (HLA)-B51 antigen was positive. A skin biopsy obtained from erythema on the left auricular cartilage showed a perichondrial infiltrate of lymphocytes admixed with histiocytes and neutrophils [Figure 2b]. The patient with oral aphthae, EN, acne-like eruptions, uveitis, and polyarthritis fulfilled criteria for diagnosis of incomplete form of BD.[7] The patient with uveitis, polyarthritis, and histological confirmation of chondritis also fulfilled criteria for diagnosis of RP.[7] From these results, we diagnosed her as MAGIC syndrome. On day 26, colchicine 0.5 mg/day was started. On day 28, the fever was declined. On day 32, serum CRP level became normal. On day 34, arthritis, the nasal and ear tenderness, and the skin eruption tended to resolve. She was discharged from the hospital. In outpatient settings, she complained that she still had a slight fever, slight arthralgia, and mildly painful erythema of the ears. Further, she had nausea potentially caused by colchicine. Therefore, on day 43, colchicine was stopped and oral administration of prednisolone 20 mg/day was started. The symptoms of MAGIC syndrome gradually disappeared. The prednisolone dosage was gradually decreased, and it was stopped on day 291. She has been in remission without active medication for a further 8 months.

Figure 1

Clinical findings at first visit (a-c) and on day 8 (d). (a) Multiple painful erythematous edematous plaques on the anterior aspect of the lower legs. (b) Small erythematous pustular lesions on the back. (c) At a high magnification of (b). (d) Painful swelling and erythema of the left ear

Figure 2

Histological studies (a and b). (a) A skin biopsy obtained from erythema on the right lower leg showed lobular, and septal panniculitis with an inflammatory infiltrate, predominantly composed of lymphocytes, which was consistent with erythema nodosum (H and E, ×100). (b) A skin biopsy obtained from erythema on the left auricular cartilage showed a perichondrial infiltrate of lymphocytes admixed with histiocytes and neutrophils, which was consistent with chondritis (H and E, ×100)

Discussion

Including our case, there have been 16 reports of MAGIC syndrome (21 patients) in the English-language published work [Table 1].[123456789101112131415] The patients (8 males and 13 females) had an age range of 10–59 years old (mean, 35.8; median, 37.0), which tends to occur at a young to early middle age. In ten evaluable cases, 6 were the white races and 4 were the yellow races. Time interval between onset of symptoms and confirmation of diagnosis ranged from 26 days to 14 years (median, 6 years), suggesting that the symptoms of MAGIC syndrome may appear within a relatively long period after the appearance of first symptoms. In 20 evaluable cases, 16 and 4 showed initial symptoms of BD and RP, respectively, suggesting that the symptoms of BD may tend to predate the appearance of RP in the course of MAGIC syndrome. Pharmacological treatment options for MAGIC syndrome were comprised of nonsteroidal anti-inflammatory drugs,[114] dapsone,[1213] colchicines,[189101115] steroids (prednisone, prednisolone, methylprednisolone, corticosteroid),[1234567891011121314] immunosuppressants (azathioprine, cyclophosphamide, methotrexate, cyclosporin A),[345679101112] and biologics (infliximab, tocilizumab).[1011121415] Although there is still no specific treatment for MAGIC syndrome, systemic steroids, immunosuppressants, and the combination therapy are considered the standard treatment for MAGIC syndrome. Recently, five cases with MAGIC syndrome treated with anti-tumor necrosis factor-alpha antibody infliximab were reported.[1011121415] Three of the five cases achieved remission and have continued to be in remission,[111214] suggesting that infliximab may be one of effective treatment options. Six cases showed aneurysm accompanied by MAGIC syndrome,[369101115] and one of the six cases died of worsening heart failure.[10] One case showed ileocecal ulcers treated with ileocecal resection followed by infliximab administration.[14] In 19 evaluable cases, the disease remission was seen in 10 patients. In the 10 remission cases, there was no description of the recurrent disease. The median follow-up period was 6.8 years (range, 9 months–21 years).

Table 1

Summary of cases of mouth and genital ulcers with inflamed cartilage syndrome

Pathogenesis of RP may involve an autoimmune reaction to Type II collagen, which is present in the sclera of the eye and in cartilage.[7] There may also be a genetic linkage to HLA-DR4 (DRB1*04 subtype alleles).[7] RP in approximately 30% is associated with other diseases including autoimmune diseases.[7] BD is a multisystem disorder associated with histopathological leukocytoclastic vasculitis and is associated with HLA-B51 in 70% of the patients.[7] However, in 5 evaluable cases,[489] only 2 cases showed HLA-B51 positivity.[8] While in 4 evaluable cases,[489] 2 cases showed HLA-DR4 positivity.[49] Some authors suggested that MAGIC syndrome is not a disease entity.[714] It may be RP occurring secondary to BD, another association of an autoimmune disease, or vasculitis with RP.[7]

In the current report, we have described a case of MAGIC syndrome that was successfully treated with oral colchicine followed by prednisolone. To the best of our knowledge, this is the latest detailed review report of MAGIC syndrome. The pathogenetic association between MAGIC syndrome, BD, and RP is still unclear, and the number of reported cases of MAGIC syndrome is insufficient to establish a clear explanation. Therefore, further accumulation of data and careful observation of the clinical course are required to improve the understanding of MAGIC syndrome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

What is new?

This is the latest detailed review report of mouth and genital ulcers with inflamed cartilage syndrome.